Lipids MINISTRY OF HEALTH - SINGAPORE
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MINISTRY OF HEALTH
SINGAPORE
Lipids
Ministry of Health, Singapore
MOH Clinical Practice Guidelines 2/2016
College of Medicine Building
16 College Road
Singapore 169854
Tel (65) 6325 9220
Fax (65) 6224 1677
www.moh.gov.sg
Chapter of Family Chapter of College of Family Singapore Endocrine &
Medicine Physicians Endocrinologists Physicians, Cardiac Society Metabolic Society
ISBN 978-981-11-1845-6 Academy of Medicine,
Singapore
Chapter of General
Physicians
Singapore of Singapore
College of Physicians,
Singapore
Dec 2016Levels of evidence and grades of recommendation
Levels of evidence
Level Type of Evidence
1 ++
High quality meta-analyses, systematic reviews of randomised controlled
trials (RCTs), or RCTs with a very low risk of bias
1+ Well conducted meta-analyses, systematic reviews of RCTs, or RCTs with a
low risk of bias
1- Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias
2 ++
High quality systematic reviews of case control or cohort studies. High
quality case control or cohort studies with a very low risk of confounding or
bias and a high probability that the relationship is causal
2+ Well conducted case control or cohort studies with a low risk of confounding
or bias and a moderate probability that the relationship is causal
2- Case control or cohort studies with a high risk of confounding or bias and a
significant risk that the relationship is not causal
3 Non-analytic studies, e.g. case reports, case series
4 Expert opinion
Grades of recommendation
Grade Recommendation
A At least one meta-analysis, systematic review of RCTs, or RCT
rated as 1+ + and directly applicable to the target population; or
A body of evidence consisting principally of studies rated as 1+,
directly applicable to the target population, and demonstrating
overall consistency of results
B A body of evidence including studies rated as 2++, directly
applicable to the target population, and demonstrating overall
consistency of results; or
Extrapolated evidence from studies rated as 1+ + or 1+
C A body of evidence including studies rated as 2+, directly applicable
to the target population and demonstrating overall consistency of
results; or
Extrapolated evidence from studies rated as 2+ +
D Evidence level 3 or 4; or
Extrapolated evidence from studies rated as 2+
GPP Recommended best practice based on the clinical experience of
(good practice the guideline development group.
points)CLINICAL PRACTICE GUIDELINES
Lipids
MOH Clinical Practice Guidelines 2/2016
APublished by Ministry of Health, Singapore 16 College Road, College of Medicine Building Singapore 169854 Printed by Kwok Printers Pte Ltd Copyright © 2016 by Ministry of Health, Singapore ISBN 978-981-11-1845-6 Available on the MOH website: http://www.moh.gov.sg/cpg Statement of Intent These guidelines are not intended to serve as a standard of medical care. Such standards are determined on the basis of all clinical data available for an individual case and are subject to change as scientific knowledge advances and patterns of care evolve. The contents of this publication are guidelines for clinical practice, based on the best available evidence at the time of development. Adherence to these guidelines may not ensure a successful outcome in every case. These guidelines should neither be construed as including all proper methods of care, nor exclude other acceptable methods of care. B
Contents
Page
Commonly used abbreviations 1
List of recommendations 2
1 Introduction 13
2 Lipids and apolipoproteins in coronary artery disease 16
3 Measurement of Lipids 19
4 Classifications of dyslipidemia 22
5 Risk assessment 25
6 Lifestyle changes 38
7 Drug therapy 43
8 Special considerations 53
9 Quality indicators for lipid management 60
References 62
Self-assessment (MCQs) 71
Workgroup members 73
CForeword It has been 10 years since the last edition of the clinical practice guideline for lipids. In that time, numerous studies have been published that have confirmed the benefits of statin therapy for the prevention of cardiovascular disease. In particular, the role of high intensity statins for individuals at the highest risk of coronary artery disease, and the roles of non-statin lipid lowering therapies has been clarified through a number of randomised controlled trials. The committee has worked hard to come up with a guideline that is as simple as possible, taking into account several recent changes in the guidelines published by organisations in other countries. I hope these guidelines will assist all doctors, particularly primary care physicians, to provide the most appropriate treatment to their patients. ASSOCIATE PROFESSOR BENJAMIN ONG DIRECTOR OF MEDICAL SERVICES D
Commonly used abbreviations
The following is a list of abbreviations commonly used in this set of guidelines
(arranged in alphabetical order), and a description of what they represent:
• ALT Alanine transaminase
• ApoA1 Apolipoprotein A1
• ApoB Apolipoprotein B
• AST Aspartate transaminase
• BNP B-type natriuretic peptide
• CAD Coronary artery disease
• DHA Docosahexaenoic acid
• eGFR Estimated glomerular filtration route
• EPA Eicosapentaenoic acide
• HDL High density lipoprotein
• HMG-CoA 3-hydroxy-3-methyl-glutaryl-CoA
• IDL Intermediate density lipoprotein
• LDL Low density lipoprotein
• Lp(a) Lipoprotein(a)
• NT-proBNP N-terminal prohormone of brain natriuretic peptide
• TC Total cholesterol
• TG Triglyceride
• VLDL Very low density lipoprotein
• FH Familial Hypercholesterolemia
1List of recommendations
Details of recommendations can be found on the indicated pages.
Key recommendations are highlighted in blue.
Measurement of lipids
Grade, CPG
Recommendation Level of page
Evidence no.
1 Clinicians should routinely screen men and women Grade B,
aged 40 years and older for lipid disorders. 19
Level 2++
2 Clinicians can routinely screen younger adults (men
and women aged 18 and older) for lipid disorders if GPP 19
they have other risk factors for CAD.
3 For individuals with screening results within the LDL
cholesterol target levels (see Table 7 page 34) and
have low TG levels, screening should be repeated
at 3 yearly intervals unless they are at very high or GPP 20
high risk of CAD, in which case screening should be
repeated annually.
4 A lipid profile should include TC, TG, LDL cholesterol
and HDL cholesterol. These should be obtained after Grade D,
21
10 to 12 hours of fasting, which is required for the Level 4
measurement of TG.
5 Routine ApoB and ApoA1 determination is not Grade D,
recommended. 17
Level 4
6 Lp(a) determination is not recommended for routine
cardiovascular disease screening. However, further
to a global cardiovascular risk assessment, Lp(a) Grade C,
18
measurements may be useful in individuals with strong Level 2+
family history of premature cardiovascular disease.
7 Physicians and patients may wish to defer lipid tests
for at least 2 weeks after a febrile illness as blood
GPP 20
lipids may be abnormal after an acute illness such as
an infection.
2Grade, CPG
Recommendation Level of page
Evidence no.
8 Patients who suffer myocardial infarction may have
depressed cholesterol levels that do not require Grade D,
20
treatment. These patients should have their blood Level 3
lipids repeated 3 months after a myocardial infarction.
Risk Assessment
Grade, CPG
Recommendation* Level of page
Evidence no.
9 The recommended LDL cholesterol target level for the
very high risk group isGrade, CPG
Recommendation* Level of page
Evidence no.
11 The recommended LDL cholesterol target level for the
intermediate risk group isLifestyle changes
Grade, CPG
Recommendation Level of page
Evidence no.
16 Patients who smoke should be advised to stop smoking Grade B,
immediately. 38
Level 2++
17 If body mass index is above 23 kg/m2, weight
Grade A,
reduction through diet modification and exercise is 38
Level 1+
recommended.
18 Persons with dyslipidemia should undertake 150 to
300 minutes per week (~30-60 minutes per day) of Grade A,
39
moderate intensity aerobic activity spread out over 5 Level 1+
to 7 days per week.
19 For good overall health, individuals who do not
currently drink should not start. For individuals who Grade C,
42
do drink, a maximum of two standard drink per day Level 2+
for women and three per day for men is recommended.
20 A diet rich in wholegrain foods, vegetables, fruit,
legumes, nuts, fish and unsaturated oils and low in Grade A,
39
saturated and trans fat, refined grains and cholesterol Level 1+
should be encouraged.
21 Dietary fibre intake should be 25-30 grams per day
by increasing consumption of whole-grains, fruit and Grade C,
40
vegetables and reducing consumption of processed Level 2+
grains and sugar.
22 Saturated fat intake should be reduced toGrade, CPG
Recommendation Level of page
Evidence no.
24 Trans fat intake should be limited to 4.5mmol/L (400mg/dL). Niacin and high Level 3
intakes of omega 3 fish oils can also be considered for
treatment of severe hypertriglyceridemia.
29 If LDL cholesterol remains elevated with fibrate Grade D,
43
therapy, a statin can be added. Level 4
6Grade, CPG
Recommendation Level of page
Evidence no.
Statins
30 In patients with pre-diabetes / impaired fasting glucose
/ impaired glucose tolerance, closer monitoring of
GPP 46
glycemic control is recommended upon initiation of
statin therapy.
31 Due to risk of myopathy and rhabdomyolysis, high
dosages of statins should be prescribed with caution,
Grade D,
especially in elderly patients, in those with impaired 46
Level 4
renal function and when a statin is combined with a
fibrate or niacin.
32 When using simvastatin, the highest dose should be
40mg. However, in patients who have been taking
Grade D,
80mg for more than 12 months without any evidence 46
Level 4
of myopathy or other side effects, it is acceptable to
continue the dose.
33 When using statins, monitor creatinine kinase in
Grade D,
patients with muscle symptoms (e.g. pain, tenderness, 47
Level 4
cramping, weakness).
34 When using statins, monitor ALT and AST in patient
Grade D,
developing symptoms suggestive of hepatotoxicity 47
Level 4
(e.g. fatigue, weakness, loss of appetite, jaundice).
35 When using statins, patients should be advised to
Grade D,
report promptly to their doctors if they develop any of 47
Level 4
the above liver or muscle symptoms.
36 Elevation in the levels of serum transaminases
above 3 times the upper limit of the normal range
Grade D,
is an indication to stop statins. The drugs can be 48
Level 4
reintroduced at a lower dose when liver function has
returned to normal.
37 Elevation of serum creatine kinase greater than 5 to
10 times the upper limit of the normal range, when
associated with muscle pain is an indication to stop
Grade D,
statins. Patients who are troubled by muscle pain, 48
Level 4
even in the absence of a raised serum creatine kinase,
may benefit from either: (i) stopping the statin therapy
or (ii) reducing the dosage.
7Grade, CPG
Recommendation Level of page
Evidence no.
Ezetimibe
38 Ezetimibe can be used as an add-on drug in
association with statins when the therapeutic target
is not achieved at the maximum tolerated statin Grade A,
49
dose, or as an alternative to statins in patients who Level 1++
are intolerant of statins or with contraindications to
statins.
Fibrates
39 Addition of fenofibrate to a statin may benefit certain
patients with Type 2 diabetes with both high TG and Grade C,
49
low HDL cholesterol dyslipidemic pattern, particularly Level 2+
those with microvascular complications.
Niacin
40 When a patient’s LDL cholesterol remains above
target despite being on the maximum tolerated dose of
Grade A,
statin, or in cases of severe hypertriglyceridemia (TG 50
Level 1+
≥4.5mmol/L or 400mg/dL) when statin therapy is not
indicated as first line therapy, niacin can be considered.
Omega 3 fish oils
41 In severe hypertriglyceridemia (e.g. TG >10mmol/L
[900mg/dL]), where fibrates alone may not adequately
Grade A,
lower the markedly elevated TG levels, omega 3 fish 50
Level 1+
oils should be added in dosages of 3 to 12 gm per day,
which contains 1-4 gm of EPA and DHA.
Combination therapies
42 The decision to combine a statin and another lipid
lowering agent must be individualised and should be
initiated only when it is strongly indicated. When statin
therapy fails to achieve LDL target on the maximum Grade D,
51
tolerated dose, consideration should be given to use Level 4
other therapies such as ezetimibe or resin as an add-on
drug to achieve the LDL target level for the patient.
8Grade, CPG
Recommendation Level of page
Evidence no.
43 Fibrates can be considered as add-on therapy to a statin
in very high or high risk patients when TG is between
2.3mmol/L (200mg/dL) and 4.5mmol/L (400mg/dL), Grade C,
in the presence of low HDL cholesterol (Special considerations
Grade, CPG
Recommendation Level of page
Evidence no.
49 Dietary management and physical activity is the Grade D,
53
mainstay of treatment for dyslipidemia in children. Level 4
50 Drug therapy should be considered only in children
aged 8 years and older with severe familial
hypercholesterolemia whose LDL cholesterol target
cannot be achieved with diet and exercise. The serum
LDL cholesterol target for children 8-10 years should Grade D,
54
beGrade, CPG
Recommendation Level of page
Evidence no.
Elderly
56 In the elderly (age>75 years), the decision to start
treatment should take into account the potential risk- Grade D,
55
reduction associated with treatment, risk of adverse Level 4
effects, drug-drug interactions, and patient preferences.
57 In very high risk elderly patients (>75 years),
physicians may wish to consider less intensive targets
(e.g. 2.6 mmol/L or 100mg/dL). When used, lipid
lowering medications in the elderly (age>75 years) GPP 56
should be started at the lowest dose and then titrated
to achieve optimal LDL cholesterol levels, in order to
avoid statin-associated side effects.
58 For patients on treatment with a statin and LDL
cholesterol < 2.1mmol/L or 80mg/dL when they turn
>75 years of age, there is no need to reduce therapy, GPP 56
if the treatment is well tolerated without any adverse
effects.
Renal disease
59 The starting dose of statins in chronic kidney disease
should be low. During therapy, serum creatine kinase GPP 56
and renal function should both be carefully monitored.
60 Fibrates can be used in patients with chronic kidney
disease in stage 1 to 3 but the dosages should be
reduced, with appropriate monitoring for side effects,
GPP 57
especially myopathy. When creatinine clearance
is less than 30 ml/min (stage 4 or 5), fibrates are
contraindicated.
Liver disease
61 Screen liver function (especially transaminases) on 2
Grade D,
consecutive occasions in patients with dyslipidemia 57
Level 4
and chronic liver disease.
11Grade, CPG
Recommendation Level of page
Evidence no.
62 In patients with dyslipidemia and chronic liver
disease, if the level of the two transaminases (ALT
and AST) is elevated but < 1.5 times the upper limit
of the normal range, statins can be given but the Grade D,
57
starting dose should be low. Careful monitoring of Level 4
the serum transaminases and creatine kinase after
commencement is recommended.
63 In patients with dyslipidemia and chronic liver disease,
if the level of the two transaminases (ALT and AST)
is between 1.5 to 3 times the upper limit of the normal
Grade D,
range, statins can still be given but with caution and 57
Level 4
the starting dose should be low. Careful monitoring
of the serum transaminases and creatine kinase after
commencement is recommended.
64 Fibrates can be given in patients whose transaminase
levels are elevated < 3 times the upper limit of the
normal range, but at a lower starting dosage. Careful GPP 58
monitoring of the serum transaminases and creatine
kinase after commencement is recommended.
Familial hypercholesterolemia
65 Screening of all first degree relatives of diagnosed
familial hypercholesterolemia patients is GPP 58
recommended.
66 Due to the high risk of CAD, a more aggressive treatment
target of LDL cholesterol of 2.1mmol/L (1 Introduction
Cardiovascular disease, especially coronary artery disease (CAD) is a
very important health problem in Singapore today. CAD is second only
to cancer as a leading cause of mortality in this country. Dyslipidemia
is one of the most important modifiable risk factors for CAD. Many
studies have demonstrated the efficacy of treating dyslipidemia, in the
prevention of CAD.
1.1 Objectives & scope of guidelines
The main aim of these guidelines is to assist physicians and other
healthcare professionals in clinical decision making by providing well-
balanced information on the management of patients with dyslipidemia,
without restricting the physician’s individual clinical judgement.
1.2 Target group
These guidelines are developed for all health care professionals, in
particular, primary care physicians, who are involved in the care of
patients with dyslipidemia.
1.3 Guidelines development
The workgroup, comprising cardiologists, endocrinologists, lipid
specialists, public health specialists and family physicians, was
appointed by MOH to develop these guidelines.
1.4 What’s new in the revised guidelines
This revision of the guideline incorporates data from several recent
randomised controlled trials that have been published since 2006. In
doing so, the committee has tried to simplify the recommendations,
wherever possible. The key revisions are in the following Chapters.
131. The chapter on risk assessment (page 25) has been revised to:
a. Do away with the previous approach of counting risk factors
as part of the algorithm for risk stratification. In its place is a 2
step process that stratifies patients into one of 4 levels of risk of
CAD (very high risk, high risk, intermediate risk and low risk).
b. Include clear guidelines for the diagnosis of familial
hypercholesterolemia and recognise that patients with familial
hypercholesterolemia are at very high risk of CAD and
therefore, should be treated aggressively.
c. Introduce chronic kidney disease as one of the risk factors to
consider when stratifying patients by risk of future CAD.
d. Recognise that patients with diabetes mellitus may not
necessarily experience the same risk as patients with established
CAD. As such, patients with diabetes can be stratified into 2
levels of risk (very high or high risk) based on the presence or
absence of chronic kidney disease.
e. Retain treat to target levels of low density lipoprotein (LDL)
cholesterol based on the risk of CAD in individual patients.
However, there is also the option for physicians to increase the
dose of statins to those used in randomised controlled trials,
even when the LDL cholesterol targets have been achieved.
2. The Chapter on lifestyle changes (page 38) has been extensively
revised to focus on areas which are supported by the strongest
evidence, including some food based dietary recommendations
(in addition to macronutrients) to help physicians support the
dietary changes necessary for patients.
3. The Chapter on drug therapy (page 43) has been revised to:
a. Emphasise that statins remain the primary lipid lowering drugs
used to reduce CAD risk, and identifies the dosage range of
statins used in randomised clinical trials in various patient
groups to guide the choice of statin and the dose.
b. Clarify the role of other lipid lowering therapies including
fibrates, niacin and ezetimibe and this clinical practice guideline
identifies situations where these drugs may be beneficial based
on recent clinical trials.
c. Provide information on over the counter preparations for lipid
lowering which has the most clearly documented effects on
blood lipids given that patients often consume such products.
These are omega 3 fish oils, red yeast rice, and plant sterols
and stanols (in the chapter on lifestyle change).
144. The Chapter on special considerations (page 53) has been revised to:
a. Provide recommendations on how to diagnose familial
hypercholesterolemia; and greater clarity on drug therapy for
children with familial hypercholesterolemia
b. Make special recommendations for the elderly to recognize the
limited data supporting the use of high intensity statins in patients
age >75 years and the need to consider the presence of other co-
morbidities, multiple medications and altered pharmacokinetics
and pharmacodynamics of drugs in these individuals. The decision
to start a statin should also take into account the life expectancy
and the quality of life of these patients.
1.5 Review of guidelines
Evidence-based clinical practice guidelines are only as current as the
evidence that supports them. Users must keep in mind that new evidence
could supersede recommendations in these guidelines. The workgroup
advises that these guidelines be scheduled for review five years after
publication, or if new evidence appears that requires substantive changes
to the recommendations. This clinical practice guideline (CPG) refers
to the CPG for “Screening for cardiovascular disease and risk factors”
(MOH CPG 1/2011). As such, revision of this CPG could be undertaken
in the event of a revision to MOH CPG 1/2011.
152 Lipids and apolipoproteins in coronary artery disease
2.1 Lipids in coronary artery disease
Blood lipid levels are important risk factors for CAD. Recently, the
Emerging Risk Factors Collaboration has carried out a large meta-
analysis to provide reliable estimates of the risk of vascular disease
associated with various lipid and apolipoprotein measures.1 Although
these studies have been conducted mostly in European and North
American populations, data from the Asia Pacific Cohort Studies
Collaboration have shown that the risk of CAD associated with
dyslipidemia in populations in Asia, are similar to those observed in
populations of European ancestry. 2, 3
The relationship between CAD and total cholesterol levels is continuous
and curvilinear. Most of the cholesterol in the blood is carried on LDL
particles, and LDL cholesterol is a well-established risk factor for CAD.
However, other lipoproteins including very low density lipoprotein
(VLDL), intermediate density lipoproteins (IDL) and lipoprotein
remnants are also atherogenic; and non-high density lipoprotein
(non-HDL) cholesterol has been used as a surrogate measure of these
atherogenic particles.4
Elevated levels of HDL cholesterol are associated with reduced risk of
CAD.5 Therefore, low HDL cholesterol is an important independent risk
factor for CAD.
Several studies suggest that elevated blood triglyceride (TG) levels are
associated with CAD.6, 7 However, the associations between TGs are
significantly attenuated after adjustment for other blood lipid levels.1
In these guidelines, total cholesterol (TC), LDL cholesterol, HDL
cholesterol and TG are used for risk stratification (Chapter 5) and for
making decisions on treatment (Chapter 7).
162.2 Apolipoproteins A1 and B
Each of the atherogenic lipoprotein particles, i.e. VLDL, IDL, LDL and
lipoprotein(a) (Lp(a)) contains one molecule each of apolipoprotein
B (ApoB). Therefore, serum concentration of ApoB reflects the total
number of these particles.
Prospective studies have found ApoB to be a better estimate of the risk of
vascular events than LDL cholesterol. Risk is highest in individuals with
ApoB levels higher than 1.2g/L and TG levels higher than 1.5mmol/L
(134mg/dL). This profile is often associated with the presence of
smaller, denser LDL particles, which are more atherogenic and
prevalent in patients with the metabolic syndrome and Type 2 diabetes.
Apolipoprotein A1 (ApoA1) is associated with HDL particles. There is
no requirement for a fasting specimen for apolipoprotein measurement.
In the INTERHEART study, the population attributable risk of raised
ApoB/ApoA1 ratio was 49.2%, compared to 35.7% for smoking, 17.9%
for hypertension and 9.9% for diabetes.8
Although the levels of ApoB and ApoA1 improves the prediction of
CAD when combined with the currently measured lipid profile, the
improvement is marginal.9 There are technical issues of reliability and
comparability of ApoB and ApoA1 assays. At this time, they should not
be routinely measured for use in global risk assessment.10
D Routine ApoB and ApoA1 determination is not
recommended.10
Grade D, Level 4
Lp(a) is an LDL particle in which ApoB is attached to the apolipoprotein
(a) protein. Apolipoprotein (a) has structural homology to plasminogen,
and competitive binding can impair fibrinolysis. Lp(a) has been
identified as an independent risk factor for CAD.11 However, there are
no available therapies targeting Lp(a) that have been shown to reduce
CAD risk or mortality.12
17C Lp(a) determination is not recommended for routine
cardiovascular disease screening. However, further to a global
cardiovascular risk assessment, Lp(a) measurements may be
useful in individuals with strong family history of premature
cardiovascular disease.11
Grade C, Level 2+
Lp(a) is an LDL particle in which ApoB is attached to the apolipoprotein
(a) protein. Apolipoprotein (a) has structural homology to plasminogen,
and competitive binding can impair fibrinolysis. Lp(a) has been
identified as an independent risk factor for CAD.11 However, there are
no available therapies targeting Lp(a) that have been shown to reduce
CAD risk or mortality.12
183 Measurement of lipids
3.1 Screening for dyslipidemia
The committee recommends that screening for dyslipidemia be carried
out in accordance with MOH CPG 1/2011 “Screening for cardiovascular
disease and risk factors”. These recommendations are as follows:
KEY RECOMMENDATION
B Clinicians should routinely screen men and women aged
40 years and older for lipid disorders.13
Grade B, Level 2++
KEY RECOMMENDATION
GPP Clinicians can routinely screen younger adults (men
and women aged 18 and older) for lipid disorders if they have
other risk factors for CAD.14
GPP
Risk factors for CAD include:14
1. Diabetes mellitus.15
2. Multiple CAD risk factors (e.g. tobacco use, hypertension,
impaired fasting glycaemia or impaired glucose tolerance16).
3. A family history of cardiovascular disease before age 50 years in
male relatives or before age 60 years in female relatives.
4. A family history suggestive of familial hyperlipidemia.
19KEY RECOMMENDATION
GPP For individuals with screening results within the LDL
cholesterol target levels (see Table 7 page 34) and have low
TG levels, screening should be repeated at 3 yearly intervals
unless they are at very high or high risk of CAD, in which case
screening should be repeated annually.
GPP
It should be noted that blood lipids may be abnormal after an acute
illness such as an infection. Hence, tests might not be accurate for at
least 2 weeks after a febrile illness.
GPP Physicians and patients may wish to defer lipid tests
for at least 2 weeks after a febrile illness as blood lipids may be
abnormal after an acute illness such as an infection.
GPP
For patients suffering from acute myocardial infarction, the cholesterol
level may be depressed between 24 hours to about 3 months after the
infarction.17-20
D Patients who suffer myocardial infarction may have
depressed cholesterol levels that do not require treatment.
These patients should have their blood lipids repeated 3 months
after a myocardial infarction.17-20
Grade D, Level 3
203.2 Lipid Measurements
KEY RECOMMENDATION
D A lipid profile should include TC, TG, LDL cholesterol
and HDL cholesterol. These should be obtained after 10 to 12
hours of fasting, which is required for the measurement of TG. 21
Grade D, Level 4
LDL cholesterol is usually calculated using the Friedewald formula22
which is as follows:
LDL cholesterol (mmol/L) = TC - (HDL cholesterol + TG/2.2)
This formula cannot be used if the TG is ≥4.5mmol/L (400mg/dL).
Direct measurement of LDL cholesterol is now available in some
laboratories in Singapore.
214 Classifications of dyslipidemia
Dyslipidemia can be classified as hypercholesterolemia, mixed
(combined) dyslipidemia, hypertriglyceridemia, and severe
hypertriglyceridemia. The classification as illustrated in Table 1 may be
helpful in deciding on the most appropriate therapy to be used (see Table
10 in Chapter 7 on drug therapy, page 44).
Table 1 Classification of dyslipidemia
Increased Concentration
Types of Dyslipidemia
Lipoprotein Serum Lipid
Hypercholesterolemia LDL TC & LDL cholesterol*
TC, LDL cholesterol* &
Mixed (Combined)
LDL & VLDL TG (1.7-4.5mmol/L
Dyslipidemia
[150-399mg/dL])
TG (1.7-4.5mmol/L
Hypertriglyceridemia VLDL
[150-399mg/dL])
Severe TG (≥4.5mmol/L
Chylomicrons
Hypertriglyceridemia [400mg/dL])
* LDL cholesterol (mmol/L) = TC - (HDL cholesterol + TG/2.2)
22Hypercholesterolemia, mixed (combined) dyslipidemia and
hypertriglyceridemia are the 3 commonest dyslipidemias. The HDL
cholesterol level is usually inversely related to the TG level and is
therefore frequently low in both mixed (combined) dyslipidemia and
hypertriglyceridemia. In severe hypertriglyceridemia, the TG levels
are extremely high, e.g. ≥4.5mmol/L (400mg/dL) but especially if
>10mmol/L (900mg/dL), due to the presence of chylomicrons. The
main complication in patients with this form of hyperlipidemia is acute
pancreatitis.
Secondary dyslipidemia may occur in the various conditions listed in
Table 2. These conditions should be excluded in any patient presenting
with dyslipidemia.
Table 2 Common causes of secondary dyslipidemia
Disorder Lipid abnormalities
Diabetes mellitus23 ↑ TG and
↓ HDL cholesterol
Chronic kidney disease24 ↑ TG
Nephrotic syndrome 25
↑ TC
Hypothyroidism 26
↑ TC
Alcohol abuse27 ↑ TG
Cholestasis27 ↑ TC
Pregnancy 28
↑ TG
Drugs e.g. diuretics, beta-blockers, oral
29
↑ TG and / or TC,
contraceptives, corticosteroids, retinoids, ↓ HDL cholesterol
anabolic steroids, progestins related to
testosterone
Although there is limited utility for clinical decision making,
dyslipidemia can also be classified at a population level to describe the
burden of dyslipidemia in the population based on the serum lipids levels
in Table 3. However, it is important to note that in making decisions for
treatment of individual patients, the primary consideration should be a
person’s risk of developing future coronary events and the appropriate
LDL cholesterol target levels associated with that level of risk.
23Table 3 Classification of total, LDL and HDL
cholesterol and triglyceride levels
Measurement in mmol/L (mg/dL) Classification
Total Cholesterol
< 5.2 (200) Desirable
5.2- 6.1 (200-239) Borderline high
≥ 6.2 (240) High
LDL Cholesterol
< 2.6 (100) Optimal
2.6-3.3 (100-129) Desirable
3.4- 4.0 (130-159) Borderline high
4.1- 4.8 (160-189) High
≥ 4.9 (190) Very high
HDL Cholesterol
< 1.0 (40) Low
1.0-1.5 (40-59) Desirable
≥ 1.6 (60) Optimal
Triglyceride
< 1.7 (150) Optimal
1.7-2.2 (150-199) Desirable
2.3- 4.4 (200-399) High
≥ 4.5 (400) Very high
245 Risk assessment
5.1 Assessment of risk status
A basic principle in the prevention of CAD is that the intensity of risk
reduction therapy should be adjusted to a person’s risk of developing
future coronary events. As such, the first step to be taken is the
assessment of the individual’s risk status and assigning individuals to
one of four risk categories. These are:
1. Very high risk
2. High risk
3. Intermediate risk
4. Low risk
5.2 Risk factors considered in assessing risk status
The following risk factors are considered in the assessment of risk status
1. Age
2. Gender
3. Ethnicity
4. Smoking
5. Blood pressure
6. Diabetes mellitus
7. Chronic kidney disease
8. The presence of CAD, atherosclerotic cerebrovascular
disease or peripheral arterial disease
For recommendations regarding the use of C-reactive protein,
homocysteine, fibrinogen and natriuretic peptides (B-type natriuretic
peptide [BNP] and N-terminal prohormone of brain natriuretic peptide
[NT-proBNP]) for the assessment of risk status, readers are referred
to MOH CPG 1/2011 “Screening for cardiovascular disease and risk
factors”.
255.3 Assessing the risk status for an individual
The following 2 steps are taken for risk stratification (see Figure 1,
page 28).
Step 1
Identify individuals who will automatically fall into the very high or
high risk groups (Table 4). For such individuals estimation of the 10-
Year CAD Risk Score is not necessary.
Table 4 Individuals at very high and high risk of
developing future coronary events
Risk Level Clinical Presentation of Individuals
Very high risk (1) Individuals with established CAD, atherosclerotic
cerebrovascular disease, aortic aneurysm or
peripheral artery disease
(2) Individuals with diabetes mellitus with chronic
kidney disease
(3) Individuals with familial hypercholesterolemia
which should be suspected in patients with low
density lipoprotein cholesterol (LDL cholesterol)
>4.9mmol/L (190mg/dL) with diagnosis based on
criteria presented on page 59).
High risk (1) Individuals with moderate to severe chronic kidney
disease (estimated glomerular filtration rate [eGFR]Step 2
For all other individuals, estimate the 10-Year CAD Risk Score using
Tables 5 (for men) or Table 6 (for women) (pages 29-32). The 10-
year CAD risk refers to the risk of having myocardial infarction or
coronary death in the next 10 years. Based on this risk score, the risk
status of the individual is classified as follows:
1. >20% - high risk
2. 10 to 20% - intermediate risk
3.Figure 1 Risk Stratification 28
Table 5-1 Estimation of 10-Year Coronary Artery Disease Risk
for Men
Age Points 1. Estimate the individual’s 10-year CAD risk
20-34 -9 by allocating points based on his age, total
35-39 -4 and HDL cholesterol levels, smoking status
40-44 0 and systolic blood pressure (BP).
45-49 3 2. Check the total points against Table 5-2
50-54 6 to estimate that individual’s 10-year CAD
55-59 8 risk.
60-64 10
65-69 11
70-74 12
75-79 13
Points
Total Cholesterol
mmol/L (mg/dL) Age Age Age Age Age
20-39 40-49 50-59 60-69 70-79
< 4.1 (160) 0 0 0 0 0
4.1-5.1 (160-199) 4 3 2 1 0
5.2-6.1 (200-239) 7 5 3 1 0
6.2-7.2 (240-279) 9 6 4 2 1
≥ 7.3 (280) 11 8 5 3 1
Points
Smoker Age Age Age Age Age
20-39 40-49 50-59 60-69 70-79
No 0 0 0 0 0
Yes 8 5 3 1 0
Points
HDL Cholesterol Systolic BP
Points
mmol/L (mg/dL) (mmHg) If untreated If treated
≥ 1.6 (60) -1 < 120 0 0
1.3-1.5 (50-59) 0 120-129 0 1
1.0-1.2 (40-49) 1 130-139 1 2
< 1.0 (40) 2 140-159 1 2
≥ 160 2 3
29Table 5-2 Estimation of 10-Year Coronary Artery Disease
Risk for Men
10-Year Risk (%)
Total Points
Chinese Malay Indian
-1 20 > 20 > 20
30Table 6-1 Estimation of 10-Year Coronary Artery Disease
Risk for Women
Age Points 1. Estimate the individual’s 10-year CAD risk
20-34 -7 by allocating points based on her age, total
35-39 -3 and HDL cholesterol levels, smoking status
40-44 0 and systolic blood pressure (BP).
45-49 3 2. Check the total points against Table 6-2
50-54 6 to estimate that individual’s 10-year CAD
55-59 8 risk.
60-64 10
65-69 12
70-74 14
75-79 16
Points
Total Cholesterol
mmol/L (mg/dL) Age Age Age Age Age
20-39 40-49 50-59 60-69 70-79
< 4.1 (160) 0 0 0 0 0
4.1-5.1 (160-199) 4 3 2 1 1
5.2-6.1 (200-239) 8 6 4 2 1
6.2-7.2 (240-279) 11 8 5 3 2
≥ 7.3 (280) 13 10 7 4 2
Points
Smoker Age Age Age Age Age
20-39 40-49 50-59 60-69 70-79
No 0 0 0 0 0
Yes 9 7 4 2 1
Points
HDL Cholesterol Systolic BP
Points
mmol/L (mg/dL) (mmHg) If untreated If treated
≥ 1.6 (60) -1 < 120 0 0
1.3-1.5 (50-59) 0 120-129 1 3
1.0-1.2 (40-49) 1 130-139 2 4
< 1.0 (40) 2 140-159 3 5
≥ 160 4 6
31Table 6-2 Estimation of 10-Year Coronary Artery Disease
Risk for Women
10-Year Risk (%)
Total Points
Chinese Malay Indian
5 20
≥ 24 > 20 > 20 > 20
325.4 Target lipid levels
In 2013, the American College of Cardiology and the American Heart
Association released a guideline on the treatment of blood cholesterol to
reduce atherosclerotic cardiovascular risk in adults in which treatment
initiation and statin dose was driven primarily by risk status and not by
LDL cholesterol level.30 This recommendation is based on randomised
controlled trials of lipid lowering for the prevention of CAD which used
fixed doses of statins, as opposed to treating patients to a specific target
as many other guidelines recommended. However, this view is not
universally accepted by physicians, even those within the United States,
at this time.
While it was noted that randomised controlled trials used fixed doses
of statins, physicians in Singapore involved in treating patients at risk
of CAD with lipid lowering therapy were of the view that there was
sufficient evidence for a causal link between LDL cholesterol and the
risk of CAD, such that a strategy to treat patients to achieve target
lipid levels (i.e. treat to target strategy) remains relevant today. This
is supported by the findings of the IMProved Reduction of Outcomes:
Vytorin Efficacy International Trial (IMPROVE-IT trial) which showed
that additional LDL cholesterol lowering provided by adding Ezetimibe
(a non-statin lipid lowering agent) to a statin resulted in further reduction
in cardiovascular events.31 It is also believed that there are patients with
relatively low risk but high LDL cholesterol who would, nevertheless,
benefit from statin therapy despite the lack of definitive evidence from
randomised clinical trials. For these reasons, the recommendations for
a treat to target strategy is retained in this edition of the clinical practice
guideline.
However, where randomised controlled trials have clearly shown a
benefit of fixed dose statin therapy, ie. in those at very high and high risk,
we have highlighted the dose of statin used in randomised controlled
trials so that that physicians can consider increasing the dose of statins
to those used in randomised clinical trials. This is particularly relevant
if the patient is not on other lipid lowering therapy (e.g. ezetimibe).
However, the physician and the patient must balance the benefits against
the cost and potential side effects of high doses of medication.
33Table 7 shows the recommended LDL cholesterol target levels in the
four risk group categories. It is important to note that the higher the risk
category, the lower will be the target LDL cholesterol level. It should
be noted that the advantage of this approach with respect to patient
outcomes has yet to be addressed in clinical trials.
Table 7 LDL cholesterol target levels in the four risk
group categories
Risk group category LDL cholesterol target level
Very high risk group < 2.1 mmol/L (80 mg/dL)
High risk group < 2.6 mmol/L (100 mg/dL)
Intermediate risk group < 3.4 mmol/L (130 mg/dL)
Low risk group < 4.1 mmol/L (160 mg/dL)
KEY RECOMMENDATION
B The recommended LDL cholesterol target level for the
Very high risk group
very high risk group isKEY RECOMMENDATION
B The recommended LDL cholesterol target level for the
High risk group
high risk group isKEY RECOMMENDATION
B The recommended LDL cholesterol target level for
Low risk group the low risk group is 10mmol/L (900mg/dL), have an
increased risk of acute pancreatitis and should be treated to reduce
the risk of pancreatitis. In these patients, the first priority is to
reduce the TG level to prevent acute pancreatitis.48
Grade C, Level 2+
KEY RECOMMENDATION
B Fibrates (but not gemfibrozil) can be considered as add-on
therapy to statins in very high or high risk patients when TG is
between 2.3mmol/L (200mg/dL) and 4.5mmol/L (400mg/dL), in
the presence of low HDL cholesterol (GPP In patients with 2 consecutive values of LDL
cholesterol levels less than 1.03mmol/L (40mg/dL), decreasing
the statin dose may be considered.
GPP
Special considerations apply to children, pregnant women,
elderly and patients with renal disease, liver disease and familial
hypercholesterolemia (Page 53).
376 Lifestyle changes
Appropriate lifestyle changes are an integral part of dyslipidemia
management. Lifestyle interventions can reduce risk of cardiovascular
disease52
6.1 Tobacco smoking
KEY RECOMMENDATION
B Patients who smoke should be advised to stop smoking
immediately.53
Grade D, Level 4
Smoking cessation has clear benefits on overall cardiovascular disease
risk54 and on HDL cholesterol.55
6.2 Weight reduction
KEY RECOMMENDATION
A If body mass index is above 23 kg/m2, weight reduction
through diet modification and exercise is recommended.56
Grade A, Level 1+
Weight reduction reduces fasting TG and increases HDL cholesterol,
with some effect on lowering of TC and LDL cholesterol.56
386.3 Exercise
KEY RECOMMENDATION
A Persons with dyslipidemia should undertake 150 to 300
minutes per week (~30 to 60 minutes per day) of moderate
intensity aerobic activity spread out over 5 to 7 days per
week.57-59
Grade A, Level 1+
Regular aerobic activity increases HDL cholesterol and reduces TG.57-59
6.4 Diet
KEY RECOMMENDATION
A A diet rich in wholegrain foods, vegetables, fruit, legumes,
nuts, fish and unsaturated oils and low in saturated and trans
fat, refined grains and cholesterol should be encouraged.60
Grade A, Level 1+
This may achieve an LDL cholesterol reduction of up to 15%.60
A Saturated fat should be replaced with mono and
polyunsaturated fats to lower TC and LDL cholesterol (without
lowering HDL cholesterol)61 and lower risk of CAD.62
Grade A, Level 1+
A Trans fat intake should be limited to < 1% of total energy or
< 2 grams per day.63
Grade A, Level 1+
Consumption of trans fat increases LDL cholesterol and reduces HDL
cholesterol.63
39GPP Saturated fat intake should be reduced to
Table 8 Examples of dietary measures for patients
Food Suggested Change
Grains Choose wholegrains instead of refined grains (e.g.
brown rice, oats, wholegrain noodles and breads)
Fruit At least two servings* per day
Vegetables At least two servings† per day
Meat, Fish and Choose oily fish (such as mackerel, pomfret, scad)
alternatives twice per week
Choose lentils, chickpeas, beans, tofu and nuts,
and fish in place of red meat
Choose white meat such as chicken instead of red
meat. If you do consume red meat (mutton, beef,
pork) choose lean cuts of meat.
Eat eggs (egg yolk) and shrimp/prawn in
moderation
Dairy foods Choose reduced or low fat dairy products
Butter and oils Choose canola, olive, peanut, corn, safflower,
sunflower, mustard and soybean oil
Limit intake of butter, ghee, palm and coconut oil
Sweets and Limit intake of sweets, cakes, soft drinks, and
sweetened drinks sweetened teas, sports, and juice drinks
Cooking Limit intake of deep fried foods and dishes
procedures cooked with coconut cream/milk
*One serve of fruit is equivalent to a small apple / orange / medium banana
or wedge of papaya or pineapple equal to 130g
†One serve of vegetables is equivalent to ¾ of a mug (100g) cooked
vegetables
416.5 Alcohol Consumption
Alcohol intake raises HDL cholesterol concentrations even at light-
to-moderate levels of intake (12.5-30 g).67 However, heavy alcohol
consumption (>60 gram per day) can increase fasting TG concentrations. 67
C For good overall health, individuals who do not currently
drink should not start. For individuals who do drink, a maximum
of two standard drink per day for women and three per day for
men is recommended. 67
Grade C, Level 2+
A standard drink is 10g of alcohol which is the equivalent of 2/3 can of
220ml beer, one small 100ml glass of wine or 1 nip (30ml) of spirits.
6.6 Plant Sterols and Stanols
Plant sterols/stanol esters are similar in structure to cholesterol and are
thought to inhibit cholesterol absorption. They can be found in fortified
fat-containing foods such as margarines and milk. Regular daily
consumption of 2g of plant sterols/stanol esters per day may reduce
LDL cholesterol up to 10% for plant sterols and up to 18% for plant
stanol esters. However, fat-soluble vitamin levels may be affected, and
long term safety data is not available.
427 Drug therapy
7.1 Choice of drugs
In considering the choice of drugs for dyslipidemia, there are 3 important
principles.
KEY RECOMMENDATION
A Statins are the first line drug for both hypercholesterolemia
(elevated LDL cholesterol) and mixed hyperlipidemia when
pharmacotherapy is indicated, except when TG > 4.5mmol/L
(400mg/dL). 38, 68
Grade A, Level 1++
KEY RECOMMENDATION
D Since patients are at increased risk for acute pancreatitis
when TG is >4.5mmol/L (400mg/dL) and the risk is greater
with higher TG level, fibrates are the first line drug to reduce the
risk of pancreatitis when TG > 4.5mmol/L (400mg/dL). Niacin
and high intakes of omega 3 fish oils can also be considered for
treatment of severe hypertriglyceridemia.48
Grade D, Level 3
D If LDL cholesterol remains elevated with fibrate therapy, a
statin can be added.21
Grade D, Level 4
7.2 Drugs used to treat dyslipidemia
Table 9 shows the important contemporary drugs and their effects on
lipid levels, and Table 10 shows the recommended drugs for the different
dyslipidemias.
43Table 9 Percentage change with the various drugs
LDL HDL
Drug TG
cholesterol cholesterol
Statins 18-55% 5-15% 7-30%
Resins 15-30% 3-5% –/
Fibrates 5-25% 10-20% 20-50%
Niacin 5-25% 15-35% 20-50%
Ezetimibe 18% 1% 8%
Omega 3 fish oils 5-10% 1-3% 15-50%
Table 10 Drugs that can be used for different dyslipidemias
Dyslipidemia Drugs of Choice
Statin, adding ezetimibe if lipids still
Hypercholesterolemia
not at target
Statin, adding ezetimibe, then fibrate
Mixed Dyslipidemia
or niacin if lipids still not at target
Fibrate, adding omega 3 fish oils or
Hypertriglyceridemia
niacin if triglyceride
(>4.5mmol/L or 400mg/dL)
>4.5mmol/L (400mg/dL)
Fibrate and omega 3 fish oils, adding
Severe hypertriglyceridemia
niacin if triglyceride
(>10mmol/L or 900mg/dL)
>4.5mmol/L (400mg/dL)
7.2.1 Statins
Statins are very effective in lowering both TC and LDL cholesterol.
Recent mega-trials have shown that statins are beneficial for both
secondary as well as primary prevention of CAD.38, 40, 45, 68-76
The approximate equipotency of the different statins is as follows: 10
mg atorvastatin = 5 mg rosuvastatin = 20 mg simvastatin = 40 mg
lovastatin / pravastatin = 80 mg fluvastatin.77, 78
44The range of daily dosages used in clinical trials examining cardiovascular outcomes in very high risk and high risk patients are outlined in Table 11. High intensity statin therapy is defined as the ability to lower LDL cholesterol by more than 50%. This is a property of the specific statin at the dose indicated and not the statin per se. Dosages below these ranges have not been used in clinical trials examining cardiovascular outcomes. Increasing the dose of medication to these levels, in pateints at very high and high risk, may be considered by the physician even if the LDL cholesterol target is achieved. However, the physician and the patient must balance the benefits against the cost and potential side effects of high doses of medication. Decreasing the statin dose may be considered when 2 consecutive values of LDL cholesterol levels are
the absolute risk reduction in the risk of cardiovascular disease in high
risk patients outweighs the possible adverse effects of a small increase
in the incidence of diabetes.81
GPP In patients with pre-diabetes / impaired fasting glucose /
impaired glucose tolerance, closer monitoring of glycemic control
is recommended upon initiation of statin therapy.
GPP
Some patients may choose supplements such as red yeast rice over
statin therapy. It is important to note that red yeast rice contains varying
amounts of compounds, including monacolins, that have 3-hydroxy-
3-methyl-glutaryl-CoA (HMG CoA) reductase inhibitor activity
(monacolin K is the active ingredient in lovastatin), and has been found
to lower TC and LDL cholesterol. Monacolin content and cholesterol-
lowering efficacy varies substantially across different commercial
preparations. Side effects are similar to that of statins. Long term safety
data is not available.
Myopathy and rhabdomyolysis
High dosages of statins are more likely to result in myopathy and
rhabdomyolysis. Although considerably rarer, rhabdomyolysis is a
much more serious complication.41
D Due to risk of myopathy and rhabdomyolysis, high dosages
of statins should be prescribed with caution, especially in elderly
patients, in those with impaired renal function and when a statin
is combined with a fibrate or niacin. 34, 79, 82, 83
Grade D, Level 4
D When using simvastatin, the highest dose should be 40mg.
However, in patients who have been taking 80mg for more than 12
months without any evidence of myopathy or other side effects, it
is acceptable to continue the dose. 34, 79, 82, 83
Grade D, Level 4
46Some statins including atorvastatin, simvastatin and lovastatin are
metabolised by the cytochrome P450 isoform 3A4. Drugs such as
erythromycin, clarithromycin, azole antifungal agents and cyclosporine
that are also metabolised by the same enzyme pathway may elevate
the serum level of these statins when administered concomitantly
and therefore may increase the risk of toxicity. Other statins such
as pravastatin are not affected as they are metabolised by other
pathways.84
Monitoring for side effects of statins
Baseline measurements of serum aspartate/alanine transaminase and
creatine kinase are recommended to establish patient’s baseline prior
to starting statin therapy. Routine repeat measurement of these are not
needed for patients who are well and asymptomatic. Monitoring of
creatinine kinase is necessary in patients with muscle symptoms (e.g.
pain, tenderness, cramping, weakness).
D When using statins, monitor creatinine kinase in patients with
muscle symptoms (e.g. pain, tenderness, cramping, weakness).79,85,86
Grade D, Level 4
D When using statins, monitor ALT and AST in patients
developing symptoms suggestive of hepatotoxicity (e.g. fatigue,
weakness, loss of appetite, jaundice).79, 85, 86
Grade D, Level 4
D When using statins, patients should be advised to report
promptly to their doctors if they develop any of the above liver or
muscle symptoms.79, 85, 86
Grade D, Level 4
47Indications for stopping statins
D Elevation in the levels of serum transaminases above 3 times
the upper limit of the normal range is an indication to stop statins.
The drugs can be reintroduced at a lower dose when liver function
has returned to normal.87
Grade D, Level 4
D Elevation of serum creatine kinase greater than 5 to 10 times
the upper limit of the normal range, when associated with muscle
pain is an indication to stop statins. Patients who are troubled
by muscle pain, even in the absence of a raised serum creatine
kinase, may benefit from either: (i) stopping the statin therapy or
(ii) reducing the dosage. 86
Grade D, Level 4
Some patients who experience muscle symptoms without elevations of
creatine kinase may experience a reduction in symptoms when switched
to an alternative statin.
7.2.2 Ezetimibe
Ezetimibe is a class of lipid lowering agents that selectively inhibits
the intestinal absorption of cholesterol and related plant sterols. When
added to a statin (e.g. simvastatin), 10 mg of ezetimibe will produce
a further 18% lowering of the LDL cholesterol. This effect is similar
to doubling the dose of the statin three times(e.g. increasing 10 mg
simvastatin to 80 mg).88 Ezetimibe is also available as a combination
tablet consisting of ezetimibe and simvastatin.89 The combination of
simvastatin and ezetimibe has been shown to reduce cardiovascular
events in patients with chronic kidney disease, compared to placebo.
In patients with established coronary artery disease, ezetimibe, when
added to a statin, produces further lowering of LDL cholesterol and
cardiovascular events.31
48A Ezetimibe can be used as an add-on drug in association with
statins when the therapeutic target is not achieved at the maximum
tolerated statin dose, or as an alternative to statins in patients who
are intolerant of statins or with contraindications to statins.31
Grade A, Level 1++
7.2.3 Resins (Bile acid sequestrants)
Resins (e.g. cholestyramine) are effective in lowering TC and LDL
cholesterol. However, they are infrequently used because of side
effects.21, 90
7.2.4 Fibrates
Commonly available fibrates in Singapore include fenofibrate and
gemfibrozil. Of these two, gemfibrozil shows greater propensity
to interact with statins when used together.91,92 See section on use of
combination therapy with statins.
C Addition of fenofibrate to a statin may benefit certain patients
with Type 2 diabetes with both high TG and low HDL cholesterol
dyslipidemic pattern, particularly those with microvascular
complications.49,50
Grade C, Level 2+
The side effects of fibrates include: (i) elevation of liver enzymes
(transaminases) (ii) myopathy and (iii) gallstones.
497.2.5 Niacin
Niacin lowers LDL cholesterol and TG effectively and can elevate HDL
cholesterol. The main side effect is flushing. Newer formulations of
extended release niacin can be better tolerated.93
A When a patient’s LDL cholesterol remains above target
despite being on the maximum tolerated dose of statin, or in cases
of severe hypertriglyceridemia (TG ≥4.5mmol/L or 400mg/dL)
when statin therapy is not indicated as first line therapy, niacin
can be considered.93
Grade A, Level 1+
In contrast, in patients with atherosclerotic cardiovascular disease
and low levels of LDL cholesterol levels 10mmol/L [900mg/
dL]), where fibrates alone may not adequately lower the markedly
elevated TG levels, omega 3 fish oils should be added in dosages
of 3 to 12 gm per day, which contains 1-4 gm of eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA).95
Grade A, Level 1+
Omega 3 fish oils can lower TC (due to lowering of TG) but has no
effect on LDL cholesterol and cardiovascular mortality96-98. Thus, they
should not be used as a substitute for statins.
507.3 Use of combination therapy with statins
D The decision to combine a statin and another lipid lowering
agent must be individualised and should be initiated only when
it is strongly indicated. 99, 100 When statin therapy fails to achieve
LDL target on the maximum tolerated dose, consideration should
be given to use other therapies such as ezetimibe or resin as an
add-on drug to achieve the LDL target level for the patient.
Grade D, Level 4
C Fibrates can be considered as add-on therapy to a statin in
very high or high risk patients when TG is between 2.3mmol/L
(200mg/dL) and 4.5mmol/L (400mg/dL), in the presence of low
HDL cholesterol (7.4 Cost-effectiveness of lipid therapy
One of the factors influencing the choice of lipid modifying drugs is
cost and cost-effectiveness. Recent studies have shown that statins and
fibrates are cost effective when used for both secondary as well as
primary prevention.38, 48, 68-74, 102-104 Importantly, most of these studies
had been done in the countries at a time when generic drugs were not
available. Today, with the wide availability of generic drugs, statin
and fibrate therapy have become even more cost-effective.103, 104
D Generic formulations cost less than non-generic drugs and
can be considered if they meet prescribed standards. 70, 103-105
Grade D, Level 4
7.5 Referral of patients to specialist
GPP Patients who remain outside the LDL cholesterol target
values or with TG levels persistently >4.5mmol/L (400mg/dL)
despite dietary changes and maximum tolerated drug therapy
should be referred to lipid specialists.
GPP
528 Special considerations
8.1 Children
GPP Routine screening for dyslipidemia is not recommended
in children. However, screening can be carried out from the age
of 2 years in children who have a first degree relative diagnosed
with familial hypercholesterolemia, as this gives the opportunity
to teach good eating habits.
GPP
D Dietary management and physical activity is the mainstay of
treatment for dyslipidemia in children.106
Grade D, Level 4
53KEY RECOMMENDATION
D Drug therapy should be considered only in children aged
8 years and older with severe familial hypercholesterolemia
whose LDL cholesterol target cannot be achieved with diet and
exercise. The serum LDL cholesterol target for children 8-10
years should be8.2 Pregnancy
GPP During pregnancy, treatment is indicated only in patients
with severe hypertriglyceridemia (e.g. TG >10mmol/L [900mg/
dL]). The only drug recommended is omega 3 fish oils after
dietary therapy.
GPP
KEY RECOMMENDATION
D Statins are contraindicated in women who are pregnant,
likely to be pregnant, or who are still breastfeeding.79, 114
Grade D, Level 4
8.3 Elderly
The elderly (age >75 years) often have co-morbidities, take
multiple medications, and have altered pharmacokinetics and
pharmocodynamics. In very high risk elderly patients (>75 years),
more intensive therapy (achieving LDL cholesterol in the range of
2.1mmol/L (80mg/dL)) has not shown benefit over less intensive
therapy. Treatment for such patients should be individualised and
special precautions need to be taken when instituting pharmacotherapy
for hyperlipidemia in elderly patients.
KEY RECOMMENDATION
D In the elderly (age >75 years), the decision to start treatment
should take into account the potential risk-reduction associated
with treatment, risk of adverse effects, drug-drug interactions,
and patient preferences.30
Grade D, Level 4
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